Purpose <p>Cachexia is a condition in which protein and energy are progressively wasted in patients with chronic kidney disease (CKD), leading to poor long-term prognosis and a decline in health-related quality of life (QOL). However, the relationship between cachexia and health-related QOL remains unclear in patients with CKD undergoing hemodialysis. This study aimed to determine the relationship between cachexia and health-related QOL in outpatients with CKD who were undergoing hemodialysis.</p> Methods <p>This cross-sectional study included outpatients with CKD who were undergoing hemodialysis. Cachexia was defined on the basis of the criteria of the Cachexia Consensus Conference, which include a minimum of 5% weight loss in 12&#xa0;months or less (or a body mass index [BMI] less than 20&#xa0;kg/m²) plus three or more of the following five diagnostic criteria: decreased muscle strength, fatigue, anorexia, low fat-free mass index, and abnormal biochemistry. The main outcome was health-related QOL, which was measured by the EuroQOL 5 dimensions 5-level. Multivariate analyses were conducted to clarify the associations between cachexia, the five diagnostic criteria items of cachexia, and health-related QOL.</p> Results <p>This study included 93 patients [age 69.4 (11.0) years; women: 49.5%]. Multivariate analysis showed that cachexia was inversely associated with health-related QOL (<i>β</i> = −0.117, <i>P</i> = 0.003). Among the five diagnostic criteria items of cachexia, only fatigue was inversely associated with health-related QOL (<i>β</i> = −0.068, <i>P</i> = 0.029).</p> Conclusions <p>Cachexia, particularly fatigue, was inversely associated with health-related QOL in patients with CKD who were undergoing hemodialysis.</p>